acute poststreptococcal glomerulonephritis an update

7/24/2019 Acute Poststreptococcal Glomerulonephritis an Update

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Acute poststreptococcal glomerulonephritis: an updateSun-Young Ahn and Elizabeth Ingulli

IntroductionGroup A b-hemolytic streptococcus (GAS) infection is

most common in children and causes a wide spectrum of

diseases, ranging from the more common superficial

infections to invasive diseases and postinfectious seque-

lae including glomerulonephritis [1]. It has been esti-

mated that over 470 000 cases of acute poststreptococcal

glomerulonephritis (APSGN) occur each year worldwide,with 97% occurring in less developed countries and

approximately 5000 cases (1% of total cases) resulting

in death[2]. Despite the fact that APSGN is one of the

most common nephritic syndromes in the world, much

remains unclear about its pathogenesis. Several putative

nephritogens have been under recent scrutiny and

possible mechanisms for their nephritogenicity have

been proposed. Host factors also play a critical role in

the development of nephritis and some recent studies

have offered additional candidates for host susceptibility.

These pathogenic factors will be addressed together with

unique clinical presentations that will facilitate prompt

diagnosis and intervention, avoiding complications.

Clinical findings and diagnosisAPSGN is characterized by the rapid onset of gross

hematuria, edema, and hypertension and is usually pre-

ceded by an episode of GAS pharyngitis or pyoderma.

Although cases of APSGN after infection with group Cand G streptococcus are known to occur[3,4], a sporadic

case of APSGN due to Streptococcus zooepidemicus was

recently reported in a young girl who likely contracted

a skin infection from contact with a horse [5]. Serologic

evidence of a recent streptococcal infection should be

sought in suspected cases of APSGN because positive

streptococcal serologies are more sensitive (94.6%)

than history of recent infection (75.7%) or positive cul-

tures (24.3%) in supporting the diagnosis [6]. APSGN

occurs most commonly in children between the ages

of 5 and 12 years; however, a recent report of APSGN

Department of Pediatrics, University of California, SanDiego and Rady Childrens Hospital, La Jolla,California, USA

Correspondence to Elizabeth Ingulli, MD, Departmentof Pediatrics, University of California, San Diego andRady Childrens Hospital, 9500 Gilman Drive, MC0815, La Jolla, CA 92093-0815, USATel: +1 858 822 4906; fax: +1 858 822 5421;e-mail:[email protected]

Current Opinion in Pediatrics 2008, 20:157162

Purpose of review

Acute poststreptococcal glomerulonephritis, the most common form of acute

glomerulonephritis in children, continues to be a major concern worldwide. This review

summarizes the recent advances in the pathogenesis, host susceptibility factors,diverse clinical presentations, and treatment of the condition.

Recent findings

Several recent advances have been made in identifying streptococcal antigens that may

play a pathogenic role in acute poststreptococcal glomerulonephritis. Nephritis-

associated streptococcal plasmin receptor and streptococcal pyrogenic exotoxin B are

currently considered major putative nephritogens. Host susceptibility factors including

HLA-DRB103011 have been found at a higher frequency in acute poststreptococcal

glomerulonephritis patients than in healthy controls. Reversible posterior

leukoencephalopathy and autoimmune hemolytic anemia are newly reported

clinical associations with the disease. Studies from developing countries question

whether the outcome is always benign. Treatment remains mostly conservative;

however, controversy exists over the use of aggressive therapy with poor prognosticfactors.

Summary

Severe group A streptococcal disease including acute poststreptococcal

glomerulonephritis remains a cause of morbidity and mortality in developing countries

and among impoverished populations. Various reports on the diverse clinical

manifestations that can be associated with the condition will aid physicians in prompt

diagnosis and intervention, while studies focusing on better understanding of

immunopathogenesis may facilitate vaccine development and prevention.

Keywords

diagnosis, outcome, pathogenesis, poststreptococcal glomerulonephritis, treatment

Curr Opin Pediatr 20:157162 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins1040-8703

1040-8703 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
mailto:[email protected]:[email protected]



in a 14-month-old demonstrated that the disease can occur

in children under 3 years, albeit rarely [7]. The low

incidence of APSGN in children under 2 years of age

may be due to the lower rate of GAS pharyngitis in this age

group and less immune complex formation.

Generalized edema due to sodium and fluid retention is

present most of the time, and may be the presentingsymptom in two-thirds of patients[8]. Respiratory distress

and pulmonary edema have been reported as the present-

ing symptoms of APSGN even in the absence of any

urinary abnormalities [9]. Chiu et al. [10] reported

six patients who presented with respiratory distress and

were initially diagnosed with pneumonia. Two of these

patients progressed to respiratory failure due to delayed

diagnosis. In a study of 152 APSGN patients, Bircan et al.

[11] reported that 44 of the patients had pulmonary edema

but were referred from local hospitals with the diagnosis of

bronchopneumonia and cardiac failure. Interestingly, only

35 of these patients had microscopic hematuria.

Hypertension, which is mainly due to fluid retention, is

found in most patients and may range from mild to

severe. It can manifest as headaches and in some cases

result in confusion and seizures. Attempts have been

made to find an association between hypertension and

atrial natriuretic peptide (ANP) and endothelin (ET), a

potent vasoconstrictor. There have been conflicting

results with one study [12] reporting that, although

ANP and ET levels were increased during the acute

phase of the disease, there was no significant correlation

between ANP/ET and blood pressure while another

study[13] demonstrated a positive correlation between

ET-1 and the height of the systolic or diastolic blood

pressure. Further studies are needed to clarify the role of

ANP and ET in hypertension in APSGN patients.

APSGN patients with encephalopathy as a result

of central nervous system vasculitis have also been

reported [14,15]. Reversible posterior leukoencephalo-

pathy syndrome, characterized by hyperintense signals in

the parieto-occipital regions on T2-weighted magnetic

resonance imaging, has also been observed in patients

with APSGN and these patients may present with de-

creased visual acuity, focal neurological signs and con-fusion that resolve with time [16,17].

The first report of autoimmune hemolytic anemia in

association with APSGN has recently been reported

[18]. Three patients, ages 3 7 years, were diagnosed

with APSGN and, during evaluation for anemia, were

found to have a positive direct antiglobulin test. In most

cases, the anemia seen in APSGN is due to hemodilution.

As described above, APSGN can present with a wide

range of symptoms that often misleads physicians, delays

diagnosis and increases morbidity. Hypertension and its

accompanying symptoms, such as headaches or seizures,

especially, are often misleading. In our experience, we

have had several patients admitted for seizures and

hypertension, who were extensively evaluated for other

diseases before APSGN was even considered, resulting in

delays in appropriate treatment. Thus, APSGN should be

considered in any patient with a history of acute onset ofedema, respiratory distress, or hypertension.

Treatment and prognosisAlthough acute renal failure with crescent formation does

occur, APSGN usually follows a benign course with

recovery of renal function and a good long-term prog-

nosis. Treatment for APSGN remains mostly supportive.

Fluid overload usually responds to diuresis and sodium

restriction. Control of hypertension is essential to reduce

morbidity and may require calcium channel blockers

in addition to loop diuretics. Although captopril has beenshown to reduce blood pressure and improve GFR in

APSGN patients, angiotensin converting enzyme inhibi-

tors should be used with caution due to possible renal

failure and hyperkalemia. Potassium exchange resin and

sodium polystyrene sulfonate can be used to treat hyper-

kalemia. In those circumstances, potassium intake should

be restricted and potassium-sparing agents should

be avoided. Occasionally, acute renal failure, severe

fluid retention unresponsive to diuretics, and intractable

hyperkalemia necessitate hemodialysis or continuous

venovenous hemofiltration. In a recent Japanese study,

complement levels normalized by 12 weeks, gross hema-

turia resolved by 13 weeks, while microscopic hema-

turia lasted up to 4 years and proteinuria up to 3 years

[19]. Persistently low C3 levels should prompt evaluation

for other causes of glomerulonephritis such as membra-

noproliferative glomerulonephritis or systemic lupus

erythematosus nephritis.

Recently, however, in a study of Aboriginal children living

in remote communities in Australia where GAS pyoderma,

is endemic, APSGN was associated with the development

of persistent proteinuria suggesting renal damage [20].

Whether intervention is necessary for those patients with

poor prognostic factors remains controversial. Proteinuria,and in particular nephrotic syndrome or an elevated crea-

tinine at presentation, is associated with a poor renal out-

come. A garland pattern of immunofluorescence of the

glomerulus on renal biopsy is associated with nephrotic

syndrome. A recent report describes a 6-year-old girl with

garland-pattern APSGN and cellular crescents who pre-

sented with acute renal failure and nephrotic syndrome

and recovered renal function with plasmapheresis and

methylprednisolonepulse therapy [21].Casesintheadult

literature of crescentic APSGN and nephrotic syndrome

treated with pulse methylprednisolone also exist [22],

158 Nephrology



suggesting that patients with poor prognostic factors such

as nephrotic proteinuria, cellular crescents on biopsy, and

renal insufficiency should receive aggressive therapy to

prevent progression to chronic kidney disease. Random-

ized controlled studies need to be performed to evaluate

the effect of aggressive therapy on long-term prognosis in

such cases.

Host susceptibility factorsPrevious studies have shown an association between

human leukocyte antigen (HLA) antigens and the inci-

dence of APSGN, suggesting the presence of host

susceptibility factors. Layrisse et al. [23] reported an

increased frequency of HLA-DRW4 in 42 unrelated

APSGN patients compared with 109 healthy controls.

More recently, in a study of Egyptian children [24],

HLA-DRB103011 was reported to be found at a signifi-

cantly higher frequency in 32 unrelated APSGN patients

compared with 380 healthy individuals (46.9 versus19.2%), although there was no correlation between the

frequency of the allele and hypertension and proteinuria.

Endothelial nitric oxide synthase gene intron 4 a/b

(eNOS4a/b) variable number of tandem repeats poly-

morphism was also found to be associated with suscepti-

bility to APSGN. The frequency of eNOS4a (eNOS4a/a

and eNOS4a/b) genotype was found to be higher in

APSGN patients than in healthy controls. Furthermore,

thea/a anda/b genotypeswere found to be a significant risk

factor for nephrotic syndrome or a glomerular filtration rate

lower than 50% of normal[25]. These findings need to be

balanced, however, with the fact that,although endothelial

nitric oxide synthase has been associated with other renal

diseases, its relation to APSGN is still unclear.

PathogenesisSeegal and Earle[26]first postulated that certain strepto-

coccalstrainscaused glomerulonephritis. Sincethen, many

nephritogenic strains have been identified as causing

glomerulonephritis[27]. Although not completely under-

stood, there are several proposed mechanisms for the

pathogenesis of APSGN [28]: circulating immune com-

plex formation with streptococcal antigenic components

and subsequent glomerular deposition along with com-plement activation; elicitation of an autoimmune response

between streptococcal components and renal components

(molecular mimicry); and alteration of a normal renal

antigen eliciting autoimmune reactivity. This review will

focus on the first two.

Immune complex deposition and complementactivationGlomerular immune complexes result from deposition

of circulating immune complexes [29] or formation of

immune complexes in situ [30]. The deposition of the

complexes and activation of the complement system is

central to the recruitment of inflammatory cells and the

induction of glomerulonephritis. The classical comple-

ment pathway is inhibited through C4b-binding protein

and the alternate pathway is predominantly activated

[31,32]. In addition, complement regulatory proteins such

as factor H and factor H-like protein (FHL-1) may beremoved by bacterial proteases thereby facilitating acti-

vation[33]. The lectin pathway was previously reported

to be a possible trigger of the alternate pathway in

APSGN [34] but recent evidence indicates that the

incidence of low complement protein mannan-binding

lectin levels (



of IL-6, TNFa, IL-8, and TGF-b1. The cytokine pro-

duction could be blocked with the addition of a poly-

clonal anti-SPE B antibody. Collectively, these findings

led to the proposal that SPE B could interact with

leukocytes and trigger a series of processes such as

cytokine production, leukocyte proliferation, and expres-

sion of adhesion molecules, thereby inducing inflam-

mation prior to the formation of immune complexes [44

].

In a recent study, Batsford et al. [45] compared the

glomerular deposition of SPEB and NAPlr (GAPDH).

They found glomerular deposits of SPE B in 12 of

17 APSGN biopsies, with circulating antibodies in all

patients (53/53 patients). On the other hand, they found

glomerular deposition of NAPlr in only one of 17 biopsies,

with circulating antibodies in only five of 47 patients.

Among 31 control biopsies, only two showed weak stain-

ing for each antigen. More importantly, they detected

immunogold-labeled SPE B deposits inside the sube-

pithelial humps, marking the first time that a strepto-coccal antigen is localized within the lesion. Their

findings support the role of zSPE B/SPE B as the more

likely nephritogenic antigen compared with NAPlr. Since

there is strong evidence for both antigens as possi-

ble streptococcal nephritogens, further study is needed

before a definitive conclusion can be reached as to which

one is predominant.

Molecular mimicryAnother proposed pathogenic mechanism for APSGN is

molecular mimicry. Some studies have shown common

antigenic determinants in the soluble fraction of nephri-

togenic streptococci and the glomerulus [4648]. Anti-

bodies to basement membrane collagen, laminin, and

glomerular heparan sulfate proteoglycan have also been

reported in the sera of patients with APSGN[49,50]. A

recent study by Luo et al. [51] suggested that the

pathogenic mechanism of SPE B might be through

molecular mimicry. They actively immunized mice with

recombinant SPE B mutant C192S, and found diffuse

glomerulonephritis with glomerular IgG and C3 deposits

in the mice. These mice also showed an elevated urinary

albumin:creatinine ratio. A panel of monoclonal anti-SPE

B antibodies was then generated and one clone, 10G, wasfound to bind to endothelial cells. Intravenous injection

of 10G into mice was found to result in glomerular

antibody and complement deposition, together with pro-

teinuria. Two endothelial cell membrane molecules,

HSP70 and thioredoxin, were recognized by 10G. From

these findings, the authors suggested that these endo-

thelial cell molecules might act as autoantigens recog-

nized by anti-SPE B antibodies, thus supporting the role

of molecular mimicry in the pathogenesis of SPE B. It is

this issue of autoimmunity associated with GAS infec-

tions that may limit vaccine development.

ConclusionAPSGN still continues to be a major health concern in

many parts of the developing world. Much progress has

been made in studying the mechanisms that lead to the

pathogenic processes in the disease, with the major

putative nephritogens NaPlr and SPE B being the center

of recent interest. Furthermore, exploration of possiblehost susceptibility factors have yielded candidates such as

HLA-DRB103011. Although APSGN is one of the most

common nephritic syndromes, it still continues to be

frequently misdiagnosed due to its diverse clinical pre-

sentations. Respiratory distress, pulmonary edema and

hypertension are most problematic and if unrecognized

could lead to a delay in treatment and increased morbid-

ity. Finally, in certain populations the outcome of

APSGN may not be as benign. Treatment for cases

of APSGN with poor prognostic factors remains contro-

versial and randomized controlled studies need to be

performed to assess the impact of different treatment

modalities on reducing the risk of end-stage renal disease.

References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as: of special interest of outstanding interest

Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (pp. 223224).

1

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This comprehensive review discusses the epidemiology, clinical features andmanagement of group Ab-hemolytic streptococcus in children and also providesa brief overview on vaccine development.

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Previous reports of APSGN caused by Streptococcus zooepidemicus, a Lance-field group Cb-hemolytic streptococcus, were of epidemics caused by contami-nated dairy products. This is thefirst case reportof a sporadic case of APSGN in achild caused by this organism, and transmitted by a horse.

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Bingler MA, Ellis D, Moritz ML. Acute poststreptococcal glomerulonephritis ina 14-month-old boy: why is this uncommon? Pediatr Nephrol2007; 22:448450.

This is an interesting case report of APSGN occurring in a 14-month-old boy. Thepossible reasons for APSGN being extremely rare in children less than 2 years ofage are discussed.

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Fujinaga S, Ohtomo Y, Umino D, et al. Pulmonary edema in a boy with biopsy-proven poststreptococcal glomerulonephritis without urinary abnormalities.Pediatr Nephrol 2007; 22:154155.

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160 Nephrology



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Fux CA, Bianchetti MG, Jakob SM, Remonda L. Reversible encephalopathycomplicating poststreptococcal glomerulonephritis. Pediatr InfectDis J 2006;25:8587.

This is one of a few case reports of the association of reversible posteriorleukoencephalopathy syndrome (RPLS) and APSGN. The authors report thatdiffusion-weighted imaging supported vasogenic edema, not cerebral vasculitis,as

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This study highlighted the potential poor outcome for patients with nephroticsyndrome and acute renal failure and the controversy regarding initiation oftreatment for rapidly progressive glomerulonephritis in such patients.

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Bakr A, Mahmoud LA,Al-Chenawi F, Salah A. HLA-DRB1 alleles in Egyptianchildren with poststreptococcal acute glomerulonephritis. Pediatr Nephrol2007; 22:376379.

This is the first reported association between the DRB1 allele and APSGN. UsingDNA-polymerase chain-reverse hybridization, the authors found that HLA-DRB103011 was present at a significantly higher frequency in APSGN patientsthan in controls.

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This is a comprehensive review of the pathogenesis of poststreptococcal glomer-ulonephritis and outlines the important new findings in the field, including theputative roles of nephritogens NAPlr and SPE B.

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35

Skattum L, Akesson P, Truedsson L, Sjoholm AG. Antibodies against fourproteins from a Streptococcus pyogenes serotype M1 strain and levels ofcirculating mannan-binding lectin in acute poststreptococcal glomerulone-phritis. Int Arch Allergy Immunol 2006; 140:919.

Previous reports have suggested that the lectin pathway may trigger the alternatepathway in APSGN. This study, however, challenges this finding by showing thateven patients deficient in mannan-binding lectin developed APSGN.

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This study showed that one of the pathogenic mechanisms of SPE B maybe inducing the release of cytokines. Human mononuclear cells were culturedwith SPE B or its precursor and several cytokines were increased in thesupernatant.

44

Mosquera J, Romero M, Viera N,et al.Could streptococcal erythrogenic toxinB induce inflammation prior to the development of immune complex depositsin poststreptococcal glomerulonephritis? Nephron Exp Nephrol 2007;105:e41e44.

This review outlines the inflammatory processes that SPE B can invoke in thekidney prior to immune complex deposition, such as cytokine production, expres-

sion of adhesion molecules and leukocyte proliferation. These processes maycomprise an important part of the pathogenesis of APSGN.

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Acute poststreptococcal glomerulonephritis Ahn and Ingulli 161



49 Kefalides NA, Pegg MT, Ohno N,et al. Antibodies to basement membranecollagen and to laminin are present in sera from patients with poststrepto-coccal glomerulonephritis. J Exp Med 1986; 163:588602.

50 Fillit H, Damle SP, Gregory JD,et al. Sera from patients with poststrepto-coccal glomerulonephritis contain antibodies to glomerular heparan sulfateproteoglycan. J Exp Med 1985; 161:277289.

51

Luo YH, Kuo CF, Huang KJ, et al. Streptococcal pyrogenic exotoxin B anti-bodies in a mouse model of glomerulonephritis. Kidney Int 2007; 72:716724.

This study explored the pathogenic mechanism of SPE B and reported that amonoclonal anti-SPE B antibody, 10G, was cross-reactive with endothelialmolecules. These findings suggest that SPE B may exert glomerular damagethrough molecular mimicry.

162 Nephrology

acute poststreptococcal glomerulonephritis an update

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